Abstract
Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.
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Acknowledgements
This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon-Italy grant number GGP07019 and grant RF-INN-2007-634163 of the Italian Ministry of Health. We thank E. Lamantea for assistance in the preparation of figures and S. Ravaglia for help in statistical analyses.
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Study design: V.T. and M.Z.; clinical evaluation and sample collection: A.B.B. and I.D.; neuroradiological evaluation: M.S.; histochemical evaluation: C.L.; biochemical assays: A.B.B. and T.H.; mouse treatment and evaluation: C.V.; statistical analysis: C.V.; manuscript writing: M.Z.; critical revision of the manuscript: C.V., V.T. and M.Z.
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Viscomi, C., Burlina, A., Dweikat, I. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med 16, 869–871 (2010). https://doi.org/10.1038/nm.2188
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DOI: https://doi.org/10.1038/nm.2188
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